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Paris, 19 march 2010

The control of HIV : a highly promising compound

A compound that can inhibit the transfer of HIV from one cell to another has been developed by researchers at the Institut de Biologie Structurale Jean-Pierre Ebel (CNRS/Université Joseph Fourier/CEA). It acts by saturating a receptor called DC-SIGN, which is used by HIV to ensure its transmission throughout the body. A patent has been filed for this compound, and an article on the subject will be published in ASC Chemical Biology on 19 March 2010.

Despite the major advances achieved in the control of
HIV, this infection still causes millions of deaths each year.The search for new cellular targets for novel
antiviral therapies remains an important challenge.

Researchers at the Institut de Biologie Structurale
(CNRS /Université Joseph Fourier/CEA)(1)have been working on a receptor called DC-SIGN which is found on the
surface of dendritic cells: immune cells which are present in contact zones
with the exterior, such as the skin or mucous membranes, and the first sites to
encounter pathogens.DC-SIGN is
implicated in the initial phases of HIV infection and constitutes a potential
therapeutic target that has not yet been exploited.

What is the role of DC-SIGN? Under normal
circumstances, it captures pathogens by recognizing certain characteristic
oligosaccharides present on their surface.The pathogens are then internalized by dendritic cells that degrade them
and present the fragments at their surface.These cells then move to lymphoid tissues where they trigger an immune
response by the body, i.e. the production of T lymphocytes that can fight the
pathogen.As for HIV, it uses DC-SIGN to
ensure its transmission in an intact form to the T lymphocytes that it will
infect.In particular, it attacks
CD4+T lymphocytes (carrying a molecule
called CD4 that is susceptible to HIV) which are the principal target used by
the virus to ensure its spread.

The researchers have developed a compound that can
inhibit the HIV transmission process to CD4+ T lymphocytes.This tetravalent compound, endowed with four
functional groups that mimic the oligosaccharides of pathogens, is recognized
by DC-SIGN, which thus prevents HIV from using the receptor to travel to the
lymphoid tissues.It has some
particularly interesting properties; e.g. high solubility in physiological
media, negligible cytotoxicity (2) and a
long-lasting effect (even after washing the cells, the inhibitory effect can
persist for several hours).Furthermore,
the simple structure of the compound means that its large-scale production
could easily be envisaged.

Last but not least, DC-SIGN is also utilized by other
pathogens to circumvent the immune system.The compound developed by the research team could also be used to
inhibit infection by the hepatitis C, dengue, Ebola and SARS (3)viruses, the Mycobacterium tuberculosis
bacterium (which causes tuberculosis) and a number of parasites.It may even prove to be more effective in
these cases than with HIV.This compound
could therefore be added to the list of antiviral compounds designed on the
basis of oside structures that exist in nature, the glycomimetics, such as
Tamiflu which is used to control seasonal influenza.

Its efficacy has been proven in vitro to prevent the
transmission of HIV from one cell to another.The researchers have protected their compound with a patent filed
jointly by CNRS and Université Joseph Fourrier. The next step is to perform
tests in animal models.Until they find
a partner, or themselves set up a structure that can manage these activities,
the researchers are continuing to enhance the efficacy of their compound to
render it more specific to DC-SIGN and increase its interaction with this
receptor.

Notes:

(1) In collaboration with Italian and Spanish researchers in the context of the European CARMUSYS Network
(2) Toxic to cells
(3) Severe acute respiratory syndrome